The DNA of mice with three alpha-thalassemias will be analyzed to determine the nature of the genetic lesions responsible for the inactivation of their adult alpha and embryonic alpha-like globin genes. Genetic crosses of thalassemic mice with inbred or exotic normal mice with variant DNA patterns will be used to produce offspring with informative DNA patterns. High molecular weight DNA will be analyzed by restriction digestion, agarose gel electrophoresis, Southern transfer, and hybridization of the genomic fragments to probes derived from bacteriophages containing cloned mouse cDNA or genomic alpha globin gene sequences. If abnormal thalassemic-DNA bands are found, they will be cloned and sequenced. These analyses should show how precisely the mouse models match the human beta- or alpha-thalassemias and how useful they may be in modeling gene therapy attempts. Mutant cell lines homozygous for the thalassemias will be created, via ectopic transfer of embryos, to be DNA sources and to be DNA recipients in genetic therapy experiments. Genetic and cytogenetic analyses will be carried out.